Surviving Mesothelioma

Overexpressed Protein Prevalent in Mesothelioma Cells: Study uncovers important link that could lead to targeted therapies

A recently published study* has revealed for the first time a connection between malignant mesothelioma and the overexpression of a particular genetic protein.

In an effort to better understand this particularly deadly form of cancer on a cellular level, a team from the University of California, San Francisco, Comprehensive Cancer Center sought to identify genetic material in mesothelioma cells that occurs at higher levels than the same material does in non-cancerous cells (that is overexpressed).

What the scientists discovered could be an important step in developing treatments that target mesothelioma cells in their earliest stages.

A strong and consistent clue

“In the biological sense, we don’t know why mesothelioma develops or why it’s so aggressive,” says primary investigator Jae Kim, MD.

“Because the molecular pathways disrupted in this disease are so different from the ones disrupted in many other cancers, we must find mesothelioma’s specific biologic mechanisms in order to come up with new targeted therapies.”

Conducting gene-expression analyses enabled the team to identify patterns of genetic expression that are unique to mesothelioma cells, as well as the specific genes involved in the disease, Kim says.

The researches looked at nine mesothelioma cell lines (tumor cells that are cultured and manipulated so that they continue to divide) and eight tumor samples (“fresh” cells derived from mesothelioma tumors).

They discovered a gene that was consistently and strongly expressed in both the cell lines and the tumor samples: stathmin, a cellular protein previously implicated in other aggressive forms of cancer.

Stathmin was overexpressed in seven of the nine cell lines, and seven of the eight tumor samples.

“We were surprised that this occurrence was so prevalent throughout our study – and that the stathmin was so strongly and consistently overexpressed in both types of mesothelioma cells,” says Kim, explaining that the protein is an important player in the life cycle of a cell.

“Stathmin’s basic role is to regulate a cell’s cytoskeleton, which controls the cell’s architecture and instructs it to grow, develop, reproduce, and divide,” he says. “Because cancer cells grow and divide much faster than normal cells do, the cytoskeleton link is critical – and many existing cancer drugs specifically target the cytoskeleton.”

Interestingly, other studies have suggested that stathmin overexpression may cause cancer cells to become less sensitive to some types of chemotherapy, Kim says,
“which could explain why mesothelioma often doesn’t respond to these agents.”

“We’re Making Progress”

The group’s findings could be valuable to the study and treatment of other types of cancer, as well, says Kim.

“Our data provide further evidence that stathmin is important in a variety of cancers – particularly the more aggressive ones – and it is definitely a target worth investigating further.”

Kim’s advice to mesothelioma patients and people at risk for the disease? Stay optimistic.

“The scientific community learns more about mesothelioma every day,” he says. “We’re discovering new molecular targets, and drugs are being developed to target different proteins and genes. We’re making progress, and people with this disease should continue to have hope.”

* Kim JY et al., Stathmin is Overexpressed in Malignant Mesothelioma. Anticancer Research, 2007 Jan-Feb;27(1A):39-44

Dr. Sugarbaker

The adage “less is more” does not necessarily apply when it comes to surgery for pleural mesothelioma. In fact, more extensive surgery can give some patients the best shot at increased longevity and quality of life.

In a 2006 article*, thoracic surgeon David J. Sugarbaker, MD, of Brigham and Women’s Hospital stated that the goal of surgery for pleural mesothelioma should always be the complete removal of all tumor tissue visible to the naked eye.

A complex disease, an ongoing debate

“Because mesothelioma can take on many forms and involve different parts of the lung, people have been comparing apples and oranges for many years” when weighing the pros and cons of surgeries for the disease, says Sugarbaker.

“We’re used to asking, ‘Do we perform a more extensive procedure or a more conservative one?’ when it comes to surgery, but that debate doesn’t apply as much to mesothelioma,” he says. “The goal should always be to remove all of the visible cancer, and then to follow the surgery with drugs that kill the cancer cells that we couldn’t see.”

The fewer mesothelioma cells that remain, the fewer cells post-surgical drug therapies will be tasked with killing – which is clearly a good thing.

What surgeons should strive for, Sugarbaker says, is a macroscopic complete resection (MCR). A few brief definitions may help explain the issue:

• Macroscopic complete resection (MCR) – The surgical removal of all tumor tissue visible to the human eye

• Extrapleural pneumonectomy (EPP) – The surgical removal of the affected lung, the covering of the heart, and the diaphragm

• Pleurectomy (P/D) – Also known as decortication, the surgical removal of tumors confined to the surface (cortex) of the lung

• Pleural mesothelioma – Mesothelioma that occurs inside the chest cavity, and makes up 90% of cases of the disease

Some tumors are limited to the surface of lung, and in those cases, MCR often can be achieved with a pleurectomy, explains Sugarbaker. But for patients with tumors that have grown down into the fissures of the lung, between the lobes, an EPP – a much more extensive procedure – may be the best choice.

“Physicians familiar with the disease process of mesothelioma understand that EPPs are not interchangeable with pleurectomies,” he says.

“The needs of the patient must drive the procedure”

So where does this leave people diagnosed with mesothelioma?

“They should understand that if a surgeon performs only one type of operation to remove mesothelioma, that surgeon may not be able to provide the most appropriate treatment for them,” Sugarbaker stresses. “Because each procedure requires specialized knowledge and experience, patients with a potentially removable tumor should look for a surgeon skilled at performing whichever procedure is necessary to achieve MCR.”

In short, “the needs of the patient – not the services offered by the surgeon – must always drive the procedure that is chosen,” he says. “My research has shown that when treated appropriately for their disease state, mesothelioma patients can live for a long time – which tells us that appropriately selected surgical procedures can make a difference.”

* Sugarbaker, DJ. Macroscopic Complete Resection: The Goal of Primary Surgery in Multimodality Therapy for Pleural Mesothelioma. J Thorac Oncol, 2006 Feb;1(2):175-6.

Understanding Mesothelioma: Molecular signaling pathways provide clues to targeted therapies

If you’re reading this article, you probably already know something about malignant mesothelioma, a particularly insidious form of cancer. What you may not know is that the scientific community is making important strides toward understanding how the disease works on a molecular level – and ultimately, toward developing therapies that treat it.

A recently published review* looks at some of the molecular signaling pathways currently being investigated.

The challenge of developing disease-specific treatments

The goal is to develop more – and more effective – treatments, says co-author Dan J. Raz, MD, of the University of California, San Francisco’s Division of Thoracic Surgery.

“The options for mesothelioma patients have primarily been surgery, conventional chemotherapy, and radiation therapy,” Raz says. “But even when a combination of treatments is used, the outcomes aren’t great.”

While several drugs have been approved for treating mesothelioma, there aren’t a lot – largely because researchers simply haven’t been able to conduct many clinical drug trials.

This is in part because, with some 5,000 Americans diagnosed with the disease annually, mesothelioma is fairly uncommon compared with other cancers. This factor, combined with mesothelioma’s typically swift progression, has made it difficult to enroll enough people in drug studies.

Another obstacle has been the large spectrum of disease. “When patients present with mesothelioma, we often don’t know how long they’ve had it, which can make it difficult to differentiate people with different levels of disease, and to know what the best treatment options might be,” Raz says.

So instead of waiting for drugs to be approved for other cancers to conduct clinical trials for their use in mesothelioma – which is how it currently works – researchers are striving to develop drugs specifically for the disease.

Which brings us back to the study of its molecular signaling pathways.

Pathways to understanding

Clinical trials of several angiogenesis drugs (those that target the blood vessels that fuel tumor growth) known to be effective for other diseases suggest that two signaling pathways examined in the article – vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) – can be disrupted by these drugs.

The review also looked at the Wnt pathway, which – because it is believed to play an important role in activating mesothelioma stem cells – also shows promise as a treatment target. By learning how to target problems in this initiating pathway, scientists may discover ways to essentially nip mesothelioma in the bud, Raz says. Several Wnt antibodies will soon enter clinical trials.

Other signaling pathways currently being studied include P53 and pRB, as well as the BCL-2 family. Also significant to the molecular makeup of mesothelioma, these pathways hold valuable clues for developing effective disease-specific therapies.

In the meantime, a number of trials for drugs developed for other cancers are underway, says Raz, and many new angiogenesis therapies are in the pipeline.

Another promising avenue – for countless medical conditions, not just cancer – is genomic medicine, of which knowledge is growing every day.

“By learning about the genetic patterns of individuals, we’ll eventually be able to know how someone’s genes interact with the biology of tumors, which signaling pathways play which roles in different people, and how patients will respond to different therapies,” Raz says. “Genetic medicine and drug development go hand in hand, and most people in the scientific community agree that this is the future of medical treatment.”

Raz encourages patients diagnosed with mesothelioma to look into clinical trials, and to seek treatment from physicians with specialized training and experience, at centers with recognized mesothelioma programs.

A growing number of centers fit the bill – UCSF, Brigham and Women’s Hospital, and Memorial Sloan Kettering Cancer Center, to name a few – which translates into more treatment options for patients.

“This is a very exciting time for advances in mesothelioma, and slow but definite progress is being made,” Raz says. “The scientific community is starting to understand a lot more about the biology of this terrible disease, which means that more targeted therapies are being introduced that could potentially help people.”

* Lee AY, Raz DJ, He B, Jablons DM, Update on the Molecular Biology of Malignant Mesothelioma. Cancer, 2007 Mar 8:109(8):1454-1461

Virotherapy Shows Promise in Treating Mesothelioma: Viruses may also be engineered to kill ovarian cancer and glioma cells

In the rapidly emerging field of virotherapy, scientists are researching many viruses as prospective agents, and many diseases as prospective targets. Mesothelioma, in particular, is long overdue for advances in treatment.

A recently published study* suggests that virotherapy may be a viable treatment option for this lethal form of cancer, as well as for other cancers.

An agent of change for patients with “no real treatment alternatives”

“Normally, viruses replicate to increase their number, and by virtue of that process, healthy cells are killed,” explains David T. Curiel, MD, PhD, director of the Division of Human Gene Therapy at the University of Alabama at Birmingham. “Virotherapy is about engineering viruses so that they replicate only in tumor cells – and kill only tumor cells.”

The catch is that in order to engineer an effective virus, scientists must first understand the molecular workings of the cancer. An adenovirus-based virotherapy agent is engineered by incorporating a tumor specific promoter (TSP) into virus genes. The TSP restricts the expression of certain genes and viral replication in tumor cells, while sparing in normal cells.

“Not much is known about the biology of mesothelioma,” Curiel says, so it was a significant step forward when his team – led by Zeng B. Zhu, MD – identified a new TSP called survivin and confirmed its relationship to mesothelioma with laboratory and animal studies. (All studies were supported by the Mesothelioma Applied Research Foundation.)

This discovery set the stage for the team to design a virotherapy agent effective against mesothelioma – a disease that has not seen an improvement in outcomes resulting from new therapies in 20 years, Curiel says – and the researchers have engineered a virus that replicates in mesothelioma cells and spares normal cells.

But while the scientific community is starting to make strides toward treating patients with mesothelioma – “a population with no real treatment alternatives,” Curiel says – and people at high risk for developing the disease, Curiel warns that “simply because we’re beginning to understand mesothelioma on this level, we shouldn’t expect to see a downtick in the number of cases.”

That’s because of mesothelioma’s long latency period. Although the disease is caused primarily by asbestos exposure – and asbestos has been disappearing in this country for a long time – mesothelioma’s life cycle and predictable demographic are such that we’ll continue to see an increase in cases for years, making the disease an ideal target for virotherapy, says Curiel.

“Mesothelioma is typically localized in the chest cavity, and virotherapy can optimize our ability to target and contain it,” he says. “We can concentrate the virus in the area where it will be most effective – and cause minimal damage to healthy cells.”

What’s next?

In addition to their virotherapy work with mesothelioma, University of Alabama researchers also have adapted an early diagnostic test for the disease, which will be the subject of future work.

There is evidence that virotherapy can be effective in treating other types of cancer, as well, Curiel says. Last month the University of Alabama at Birmingham got FDA approval to begin investigating the use of virotherapy as a treatment for ovarian cancer, and a national clinical trial will begin in May.

Alabama researchers are also collaborating with scientists at MD Anderson Cancer Center and the Free University of Amsterdam to investigate the efficacy of virotherapy in treating glioma, an aggressive form of brain cancer.

So stay tuned. And speak with your doctor to learn more about virotherapy and cancer.

* Zhu et al, Targeting Mesothelioma Using an Infectivity Enhanced Survivin-Conditionally Replicative Adenoviruses. J Thorac Oncol. 2006 Sep; 1(7):701-711.

Is there a connection between survival and immunity?

Paul Kraus – Ten Year Mesothelioma Survivor

In 1997, Paul Kraus was diagnosed with widely disseminated mesothelioma. The prognosis was poor – a few months at best. Not ready to give up, he consulted with various physicians and conducted his own research. From this information he created his own path to healing which involved boosting his immune system with integrative therapies, alternative treatments, dietary changes, and mind-body approaches. As he maintained his health and quality of life from weeks to months and then from months to years, many were interested in what he did.

Mesothelioma, the asbestos related cancer, is a particularly insidious disease. Unlike other cancers that have a typical survival measured in years, the median survival with mesothelioma is often measured in months.

As a result of his miraculous survival, Mr. Kraus wrote a book called “Surviving Mesothelioma and Other Cancers: A Patient’s Guide.” After reviewing the book, Dr. Bernie Siegel remarked that, “Paul Kraus’ book has all the information a cancer patient needs to have in order to learn what survival behavior is about…”

But, Mr. Kraus is not alone. There are other long-term mesothelioma survivors. A cursory review of the medical-scientific literature identified various survivors who lived decades after they were diagnosed. Of course the bigger question is Why?

Other Long Term Mesothelioma Survivors

In 1994, a 58 year old man was diagnosed with malignant pleural mesothelioma. He had a left thoracotomy, multiple pleural biopsies, and chest wall resection. As of 2007, he is still alive.1 In 1986, a 65 year-old women was diagnosed in mesothelioma and lived for 14 years with no treatment other than radiation at the end.2 In 1970, a 53 year-old man who had worked at a plant adjacent to the Brooklyn Navy Yard, where asbestos was used, was diagnosed with mesothelioma. Other than thoracotomy, no treatment was provided. A medical article was published about him in 1978 and he was reported as still doing well.3 These are just three examples. There are others.

The Role of the Immune System – What Do Long-Term Survivors Have in Common?

What is striking is that some of the scientific reports allude to the fact that the patient’s immune system may have played a role in their recovery. In writing about the 58 year-old man, doctors suggested that the “spontaneous regression may be an immune-mediated phenomenon.” And in the article about the individual who had worked at a plant adjacent to the Brooklyn Navy Yard, physicians wrote, “Our findings are consistent with the concept that normal immunological function may effectively impede dissemination of the disease (malignant pleural mesothelioma).”

Scientists and clinicians are currently testing a variety of immunotherapies for the treatment of mesothelioma. These treatments are designed to artificially improve the performance of a patient’s immune system using various proteins. Some of these therapies have already demonstrated promise compared to the conventional approaches of surgery, chemotherapy, and radiation.

For example in a clinical trial involving immunotherapy and chemotherapy, the median survival was reported at 29.2 months4 and in another immunotherapy trial the median survival was 15 months.5 This may not sound like a lot, but keep in mind that median survival with the best conventional therapies is about 9-12 months.

Mesothelioma and the Immune System

This raises the question - does the immune system play a role in controlling malignant mesothelioma? Paul Kraus’ experience and those of other long-term mesothelioma survivors suggests that such a role may be possible. If proven true, this may also address other intriguing questions. For example, why does mesothelioma evolve from asbestos many decades after exposure – did the patient’s immune system help keep it in check until a certain time? And why are only a few people who are exposed to asbestos ultimately diagnosed with mesothelioma – was their immune system able to protect them from the disease throughout their life?

The treatment approaches used by long-term mesothelioma survivors like Paul Kraus may ultimately help answer these critical questions.

Listen to Mesothelioma Survivor

For more information about attending the Paul Kraus Teleconference on April 26 at 5 PM (PT) 8 PM (ET) call 1-619-261-7922 or go to http://www.survivingmesothelioma.com/index.cfm for more information.

Endnotes

(1) Pilling, J.E., et al., “Prolonged Survival Due to Spontaneous Regression and Surgical Excision of Malignant Mesothelioma.” Ann Thorac Surg, 2007; 83: 314-5.

(2) Wong, C.F., et al., “A Case of Malignant Pleural Mesothelioma with Unexpectantly Long Survival without Active Treatment.” Respiration March/April 2002; 69, 2: 166-168.

(3) Fischbein, A,. et al., “Unexpected Longevity of a Patient with Malignant Pleural Mesothelioma.” Cancer 1978; 42:1999-2004.

(4) Monnet I, et al., “Intrapleural infusion of activated macrophages and gamma-interferon in malignant pleural mesothelioma: a phase II study.” Chest. 2002 Jun;121(6):1921-7.

(5) Castagneto B, et al., “Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients.” Lung Cancer. 2001 Feb-Mar;31(2-3):303-10.